It is widely held that normal glucose and insulin dynamics must be restored to optimally treat diabetes. Several new insulin replacement approaches are under development, including encapsulated islet devices, pancreas transplantation, mechanical insulin pumps with or without an implanted glucose sensor, and multiple daily insulin injections by conventional means with frequent blood glucose sampling. Each of these replacement approaches has characteristic glucose sensitivities, insulin delivery kinetics, and insulin delivery location that can be specified to some extent, but there are serious reservations about the insulin dynamics and quality of control that may be achievable. Moreover, no detailed dynamic performance goals are presently available to specify the ideal output. We maintain that the dynamics and control achieved by the natural endocrine pancreas should serve as performance standards for these replacements. Unfortunately, very little is known about the dynamic response of the natural pancreas or its range of normal variation. The objectives for this revised project are: (1) Experimentally define in detail the intrinsic first pass input-output dynamics of the normal dog pancreas, with glucose as the input and insulin as the output. This will include the effects of certain other biochemicals, the role of the liver, and the resulting portal, post-hepatic and mixed venous blood concentration dynamics. (2) Develop a faithful input-output model of the endocrine pancreas, the pancreas-liver system and the resulting output blood glucose and insulin concentrations. And (3) a new and important aspect of this revised application, evaluate a novel method of portal vein access for insulin delivery. In subsequent funding periods we will experimentally determine portal vein and systemic blood glucose and insulin concentrations that result when insulin is administered from potential replacement sites, including subcutaneous tissues (mimicking injection), the peritoneum (pumps and encapsulated islet devices), and the abdominal aorta (transplantation). This timely project will provide key information about how to most effectively implement insulin replacement technologies.